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A Phase I/II Study of MLN8237, an Oral Selective Small Molecule Inhibitor of Aurora A Kinase, in Children With Relapsed/Refractory Solid Tumors


Phase 1/Phase 2
1 Year
21 Years
Open (Enrolling)
Both
Leukemia, Neuroblastoma, Unspecified Childhood Solid Tumor, Protocol Specific

Thank you

Trial Information

A Phase I/II Study of MLN8237, an Oral Selective Small Molecule Inhibitor of Aurora A Kinase, in Children With Relapsed/Refractory Solid Tumors


OBJECTIVES:

Primary

- To estimate the maximum tolerated dose and recommended phase II dose of Aurora A kinase
inhibitor MLN8237 administered once daily or twice daily in pediatric patients with
relapsed or refractory solid tumors (except CNS tumors) or acute lymphoblastic leukemia
(ALL). (ALL closed to accrual as of 02/18/10)

- To evaluate the toxicity of this drug in these patients.

- To characterize the pharmacokinetics of this drug in these patients.

Secondary

- To determine the antitumor activity of this drug in these patients. (Phase I)

- To determine the efficacy of this drug, using the once daily dosing schedule, in these
patients. (Phase II)

- To explore the relationship between polymorphic variations in the
UDPglucuronyltransferase gene UGT1A1 and exposure to MLN8237.

- To assess two common polymorphic variants in the Aurora A kinase gene (Phe31Ile and
Val57Ile) thought to potentially influence tumorigenesis.

- To examine the relationship between Aurora A expression status and response to Aurora A
inhibition.

OUTLINE: This is a multicenter phase I, dose escalation followed by a phase II study.
Patients are stratified according to diagnosis (solid tumors vs neuroblastoma vs acute
lymphoblastic leukemia). (Acute lymphoblastic leukemia closed to accrual as of 02/18/10)

Patients receive oral Aurora A kinase inhibitor MLN8237 once or twice daily on days 1-7.
Courses repeat every 21 days for up to 24 months in the absence of disease progression or
unacceptable toxicity.

Whole blood samples are collected from all patients for genotyping for polymorphisms in
UGT1A1 enzymes and polymorphisms in the Aurora A kinase gene. For patients in the phase II
portion of the study, previously preserved tumor tissue blocks and bone marrow or peripheral
blasts are evaluated for Aurora A kinase protein using IHC, mRNA expression, and gene
amplification using FISH or quantitative PCR. Bone marrow is also obtained for FAB
morphology, immunophenotyping, and cytogenetics. Blood samples are also collected
periodically during the first course of therapy for pharmacokinetics studies.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed solid tumor (phase I, stratum A1 or A2) or neuroblastoma
(phase II, stratum B) or relapsed/refractory acute lymphoblastic leukemia (ALL)
(phase II, stratum C) (ALL closed to accrual as of 02/18/10)

- Relapsed or refractory

- Patients with leukemia who relapse during standard maintenance therapy are
eligible at time of relapse (closed to accrual as of 02/18/10)

- Meets the following criteria for measurable or evaluable disease as defined below by
stratum:

- Stratum A1 or A2: measurable or evaluable disease

- Stratum B: meets 1 of the following criteria:

- Measurable tumor on MRI, CT scan, or x-ray obtained within 4 weeks prior to
study entry

- Evaluable tumor by MIBG scan or bone marrow involvement with tumor cells
seen on routine morphology

- Stratum C: must have M3 bone marrow (closed to accrual as of 02/18/10)

- No existing curative therapy for the disease or therapy proven to prolong survival
with an acceptable quality of life

- No CNS tumors, known CNS metastatic disease, or known CNS leukemia

PATIENT CHARACTERISTICS:

- Karnofsky performance status (PS) 50-100% (patients > 16 years of age) OR Lansky PS
50-100% (patients ≤ 16 years of age)

- Patients with solid tumors (phase I, stratum A1 or A2) must meet the following
hematopoietic criteria:

- ANC ≥ 1,000/μL

- Platelet count ≥ 100,000/μL (no platelet transfusions within 7 days prior to
enrollment)

- Hemoglobin ≥ 8.0 g/dL (transfusion allowed)

- Patients in phase II portion of the study (stratum B & C) must meet the following
hematopoietic criteria: (stratum C closed to accrual as of 02/18/10)

- ANC ≥ 750/μL

- Platelet count ≥ 50,000/μL (transfusion allowed)*

- Hemoglobin ≥ 8.0 g/dL (transfusion allowed)* NOTE: * Patients with leukemia must
not be refractory to red blood cell or platelet transfusions (closed to accrual
as of 02/18/10)

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70ml/min OR serum
creatinine based on age/gender (male [M], female [F]) as follows (in mg/dL):

- 0.6(M), 0.6(F) (for patients 1 to < 2 years of age)

- 0.8(M), 0.8(F) (for patients 2 to < 6 years of age)

- 1(M), 1(F) (for patients 6 to < 10 years of age)

- 1.2(M), 1.2(F) (for patients 10 to < 13 years of age)

- 1.5(M), 1.4(F) for patients 13 to < 16 years of age)

- 1.7(M), 1.4(F) (for patients 16 years of age and over)

- Bilirubin ≤ 1.5 times upper limit of normal (ULN) for age

- ALT ≤ 5.0 times ULN for age

- Serum albumin ≥ 2 g/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No uncontrolled infection

- Patients must be able to swallow capsules

- No patients who are unable to comply with the safety monitoring requirements of the
study, in the opinion of the investigator

PRIOR CONCURRENT THERAPY:

- Recovered from prior chemotherapy, immunotherapy, or radiotherapy

- More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea)
(stratum A1 or A2)

- At least 14 days since prior cytotoxic therapy

- At least 24 hours since cytoreduction with hydroxyurea

- At least 7 days since prior hematopoietic growth factor therapy

- At least 7 days since prior biological therapy (anti-neoplastic agent)

- At least 2 weeks since prior local palliative external radiotherapy (XRT) (small
port)

- At least 6 weeks since prior treatment with therapeutic doses of iodine I 131
metaiodobenzylguanidine

- At least 6 months since prior total-body irradiation (TBI), craniospinal XRT, or
radiation to more than 50% of pelvis

- At least 6 weeks since prior other substantial bone marrow radiation

- At least 3 months since prior stem cell transplant or rescue without TBI AND no
evidence of active graft vs host disease

- At least 3 half-lives since prior therapy that includes a monoclonal antibody

- More than 7 days since prior growth factors that support platelet or white cell
number or function

- Concurrent corticosteroids allowed provided patient is on a stable or decreasing dose
of corticosteroid for ≥ 7 days prior to study enrollment

- No other concurrent investigational drug

- No other concurrent anticancer therapy, including chemotherapy, radiotherapy,
immunotherapy, or biological therapy

- Concurrent intrathecal methotrexate allowed for patients with ALL at the
discretion of the treating investigator

- No concurrent P-gp substrates (i.e., digoxin, cyclosporine, tacrolimus, or sirolimus)

- No concurrent chronic benzodiazepines

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose and recommended phase II dose of Aurora A kinase inhibitor MLN8237 administered once daily or twice daily (Phase I)

Safety Issue:

Yes

Principal Investigator

Yael P. Mosse, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Hospital of Philadelphia

Authority:

United States: Federal Government

Study ID:

CDR0000610257

NCT ID:

NCT00739427

Start Date:

September 2008

Completion Date:

Related Keywords:

  • Leukemia
  • Neuroblastoma
  • Unspecified Childhood Solid Tumor, Protocol Specific
  • unspecified childhood solid tumor, protocol specific
  • recurrent neuroblastoma
  • recurrent childhood acute lymphoblastic leukemia
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Neuroblastoma
  • Neoplasms

Name

Location

Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Children's Hospital of Orange CountyOrange, California  92668
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Hospital and Regional Medical Center - SeattleSeattle, Washington  98105
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - DallasDallas, Texas  75390
Baylor University Medical Center - HoustonHouston, Texas  77030-2399
Indiana University Melvin and Bren Simon Cancer CenterIndianapolis, Indiana  46202-5289
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer InstituteBoston, Massachusetts  02115
C.S. Mott Children's Hospital at University of Michigan Medical CenterAnn Arbor, Michigan  48109-0286
Masonic Cancer Center at University of MinnesotaMinneapolis, Minnesota  55455
Siteman Cancer Center at Barnes-Jewish Hospital - Saint LouisSt. Louis, Missouri  63110
Herbert Irving Comprehensive Cancer Center at Columbia University Medical CenterNew York, New York  10032
Knight Cancer Institute at Oregon Health and Science UniversityPortland, Oregon  97239-3098
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
UAB Comprehensive Cancer CenterBirmingham, Alabama  35294